Inducible Tertiary Lymphoid Structures: Promise and Challenges for Translating a New Class of Immunotherapy

Abstract

Tertiary lymphoid structures (TLS) are ectopically formed aggregates of organized lymphocytes and antigen-presenting cells that occur in solid tissues as part of a chronic inflammation response. Sharing structural and functional characteristics with conventional secondary lymphoid organs (SLO) including discrete T cell zones, B cell zones, marginal zones with antigen presenting cells, reticular stromal networks, and high endothelial venues (HEV), TLS are prominent centers of antigen presentation and adaptive immune activation within the periphery. TLS share many signaling axes and leukocyte recruitment schemes with SLO regarding their formation and function. In cancer, their presence confers positive prognostic value across a wide spectrum of indications, spurring interest in their artificial induction as either a new form of immunotherapy, or as a means to augment other cell or immunotherapies. Here, we review approaches for inducible (iTLS) that utilize chemokines, inflammatory factors, or cellular analogues vital to TLS formation and that often mirror conventional SLO organogenesis. This review also addresses biomaterials that have been or might be suitable for iTLS, and discusses remaining challenges facing iTLS manufacturing approaches for clinical translation.

Keywords: bioengineering; biomaterials; cancer; immunotherapy; tertiary lymphoid structure (TLS).

Figure 1

A summary schematic of potential therapeutic use of inducible tertiary lymphoid structures (iTLS). iTLS preparations may include cellular components such as dendritic cells, or reticular fibroblasts modified to engage the LTBR pathway, or co-delivered with soluble LTBR-ligands via a delayed-release platform such as liposomes, nanoparticles, or micelles. Injectable or implantable iTLS preparations could be administered at the site of tumor resection to induce TLS and subsequently control residual disease or counteract reoccurrence.